RESUMEN
The gene encoding the transcriptional co-activator MN1 is the target of the reciprocal chromosome translocation (12;22)(p13;q12) in some patients with acute myeloid leukemia (AML). In addition, expression array analysis showed that MN1 was overexpressed in AML specified by inv(16), in some AML overexpressing ecotropic viral integration 1 site (EVI1) and in some AML without karyotypic abnormalities. Here we describe that mice receiving transplants of bone marrow (BM) overexpressing MN1 rapidly developed myeloproliferative disease (MPD). This BM also generated myeloid cell lines in culture. By mimicking the situation in human inv(16) AML, forced coexpression of MN1 and Cbfbeta-SMMHC rapidly caused AML in mice. These findings identify MN1 as a highly effective hematopoietic oncogene and suggest that MN1 overexpression is an important cooperative event in human inv(16) AML.
Asunto(s)
Inversión Cromosómica , Cromosomas Humanos Par 16/genética , Regulación Neoplásica de la Expresión Génica/fisiología , Leucemia Mieloide/etiología , Proteínas Oncogénicas/genética , Translocación Genética/genética , Enfermedad Aguda , Animales , Trasplante de Médula Ósea , Células Cultivadas , Femenino , Citometría de Flujo , Humanos , Leucemia Mieloide/metabolismo , Leucemia Mieloide/patología , Ratones , Ratones Transgénicos , Trastornos Mieloproliferativos/etiología , Trastornos Mieloproliferativos/metabolismo , Trastornos Mieloproliferativos/patología , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Tasa de Supervivencia , Transactivadores , Proteínas Supresoras de TumorRESUMEN
MN1-TEL is the product of the recurrent t(12;22)(p12;q11) associated with human myeloid malignancies. MN1-TEL functions as an activated transcription factor, exhibiting weak transforming activity in NIH3T3 fibroblasts that depends on the presence of a functional TEL DNA-binding domain, the N-terminal transactivating sequences of MN1 and C-terminal sequences of MN1. We determined the transforming activity of MN1-TEL in mouse bone marrow (BM) by using retroviral transfer. MN1-TEL-transduced BM showed increased self-renewal capacity of primitive progenitors in vitro, and prolonged in vitro culture of MN1-TEL-expressing BM produced immortalized myeloid, interleukin (IL)-3/stem cell factor-dependent cell lines with a primitive morphology. Transplantation of such cell lines into lethally irradiated mice rescued them from irradiation-induced death and resulted in the contribution of MN1-TEL-expressing cells to all hematopoietic lineages, underscoring the primitive nature of these cells and their capacity to differentiate in vivo. Three months after transplantation, all mice succumbed to promonocytic leukemia. Transplantation of freshly MN1-TEL-transduced BM into lethally irradiated mice also caused acute myeloid leukemia within 3 months of transplantation. We infer that MN1-TEL is a hematopoietic oncogene that stimulates the growth of hematopoietic cells, but depends on secondary mutations to cause leukemia in mice.
Asunto(s)
Transformación Celular Neoplásica , Cromosomas Humanos Par 12 , Cromosomas Humanos Par 22 , Células Madre Hematopoyéticas/patología , Leucemia Mieloide/genética , Proteínas de Fusión Oncogénica/genética , Factores de Transcripción/genética , Translocación Genética , Animales , Proliferación Celular , Trasplante de Células , Humanos , Leucemia Mieloide/patología , Ratones , Ratones Endogámicos C57BLRESUMEN
Fusion genes encoding the 3' part of the can gene are implicated in two types of leukemia. The dek-can fusion gene is present in t(6;9) acute myeloid leukemia and the set-can fusion gene is present in one case of acute undifferentiated leukemia. In order to obtain leads towards the molecular basis of these diseases, we have studied the cellular localization of the DEK-CAN and SET-CAN fusion proteins and their normal counterparts. DEK-CAN and SET-CAN were localized exclusively in the nucleus, and also DEK and SET were found to be nuclear proteins. However, CAN was mainly located at the nuclear and cytoplasmic face of the nuclear envelope. This observation is in accordance with the presence of an amino acid repeat in the C-terminal part of CAN, common to the family of nucleoporins. The C-terminal part also contains a nuclear location domain as shown by deletion analysis. This domain may be important for the presence of CAN at the nucleoplasmic side of the nuclear envelope. The relocation of the carboxyterminal part of CAN due to DEK-CAN and SET-CAN may reinforce a nuclear function of the CAN protein.